Effects of naltrexone on food intake and body weight gain in olanzapine-treated rats

Blockade of opioidergic neurotransmission contributes to reduction in body weight. However, how such blockade affects body weight gain (BWG) attributed to second generation antipsychotic agents (SGAs) has not yet been established. Here we examined the effects of an opioid receptor antagonist, naltrexone (NTX), on food intake and BWG associated with an SGA, olanzapine (OL). Four groups of Wistar Han IGS rats were treated for 28 days with either OL (2 mg/kg twice daily, intraperitoneal (IP)), a combination of OL (2 mg/kg twice daily, IP) + extended-release NTX (50 mg/kg, one-time, intramuscular (IM)), extended-release NTX (50 mg/kg, one-time, IM) or vehicle and their food intake and body weight were measured daily for the first nine days and every other day thereafter. Food intake and BWG that were increased by OL were decreased by the added NTX while NTX alone had no significant effects on food intake or on BWG. Plasma leptin concentrations were significantly elevated in the three groups receiving pharmacological agents, but did not differ among each other, suggesting that changes in leptin secretion and/or clearance alone would not explain the food intake and the body weight findings. Our results extend prior reports on anorexigenic effects of opioid antagonists by demonstrating that such effects may generalize to food intake increases and BWG arising in the context of OL pharmacotherapy.     

Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: a double-blind placebo-controlled study

Rationale Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics (SGAs) is imperative. In the present study, we sought to replicate our preliminary findings, which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Materials and method Fifty-nine patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in this randomized double-blind study. Reboxetine (4 mg/day; 31 patients) or placebo (29 patients) was coadministered with olanzapine (10 mg/day) for 6 weeks. Analysis was by intention-to-treat. Results Nine patients in each group prematurely discontinued the trial. Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight (mean = 3.31 kg, SD = 2.73) than their olanzapine/placebo-treated counterparts (mean = 4.91 kg, SD = 2.45). Significantly fewer olanzapine/reboxetine-treated patients gained at least 7% of their initial weight, the cutoff for clinically significant weight gain (6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients). Seven (22.6%) olanzapine/reboxetine-treated patients compared to only one patient (3.6%) in the olanzapine/placebo group revealed no weight change or even modest weight loss. Appetite increase was significantly lower in the olanzapine/reboxetine than olanzapine/placebo group and was correlated with attenuation of weight gain. Reboxetine addition was safe and well tolerated. Conclusions The results confirm that coadministration of reboxetine promotes a clinically meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients. If substantiated in long-term studies, along with behavioral management and diet counseling, reboxetine may have a clinical utility in controlling SGA-induced weight gain.     

Weight changes on fluoxetine as a function of baseline weight in depressed outpatients

In order to test the hypothesis that weight changes on fluoxetine are a function of baseline weight, we divided a group of 39 depressed outpatients into 3 groups based on the Fogarty table: ideal, underweight, and overweight. Subjects were participants in an open label depression trial that was carried out over 3 years. Doses ranged from 20 mg to 80 mg depending on the patients' response and side effect profile. Demographic data, weights and Hamilton Rating Scale for Depression (HAM-D) scores were collected at baseline. Subsequent Hamilton scores and weights were obtained at monthly intervals until the subjects were terminated from the study. Only those subjects who remained in the study for at least 6 months were included in this analysis. Overweight subjects showed a significant weight loss of 3.3 lbs (p less than .001) in the first 2 months whereas ideal weight subjects gained 4.4 lbs (p = .02) over a 4-month period. All of these changes were maintained throughout the study. The underweight patients showed no consistent trends. All patients examined (those who completed 6 months or more in the trial) had significant decreases in their HAM-D scores (p less than .001).     

Effects of fluoxetine on the polysomnogram in outpatients with major depression.

This study investigated the effects of open-label fluoxetine (20 mg/d) on the polysomnogram (PSG) in depressed outpatients (n = 58) who were treated for 5 weeks, after which dose escalation was available (< or = 40 mg/d), based on clinical judgment. Thirty-six patients completed all 10 weeks of acute phase treatment and responded (HRS-D < or = 10). PSG assessments were conducted and subjective sleep evaluations were gathered at baseline and at weeks 1, 5, and 10. Of the 36 subjects who completed the acute phase, 17 were reevaluated after 30 weeks on continuation phase treatment and 13 after approximately 7 weeks (range 6-8 weeks) following medication discontinuation. Acute phase treatment in responders was associated with significant increases in REM latency, Stage 1 sleep, and REM density, as well as significant decreases in sleep efficiency, total REM sleep, and Stage 2 sleep. Conversely, subjective measures of sleep indicated a steady improvement during acute phase treatment. After fluoxetine was discontinued, total REM sleep and sleep efficiency were found to be increased as compared to baseline.     

Early weight gain as a predictor of substantial weight gain with olanzapine/fluoxetine combination: an analysis of 2 adult studies in treatment-resistant depression

Weight gain during olanzapine/fluoxetine combination (OFC) therapy is very common. We examined early (at 2 weeks) weight gain as a predictor of later (at 26 weeks) substantial weight gain in patients with treatment-resistant depression during OFC pharmacotherapy. Data were analyzed from 2 studies (Study 1 and Study 2)-each with an acute, double-blind phase and an open-label phase-in patients who completed 26 weeks of open-label treatment (N = 306). Mean patient age was 46 years; the majority was female and white. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were examined using early weight gain of 2 kg or more as a predictor of 10 kg or more substantial weight gain. Sensitivity (true positive rate) and specificity for Study 1 (n = 73) were 33% and 71%, respectively; PPV and NPV were 23% and 80%, respectively. Sensitivity and specificity for Study 2 (n = 233) were 52% and 70%, respectively; PPV and NPV were 31% and 85%, respectively. Overall, in the 2 trials analyzed, for patients who did not gain 2 kg or more (2.54 lb) in the first 2 weeks of OFC treatment, the observed frequency was 16.3% for gaining 10 kg or more at 26 weeks. Compared to those with early weight gain, patients without early weight gain were less likely to have substantial weight gain after OFC treatment. Additional research is needed to further explore the predictive power of early weight gain for subsequent substantial weight gain in patients with treatment-resistant depression treated with OFC.     

Acute weight gain induced by amisulpride monotherapy in a first-episode schizophrenic patient

The introduction of atypical antipsychotics into clinical practice has lead to an increase of adverse metabolic effects in psychotic patients. Amisulpride is a substituted benzamide derivative, and its use is associated with a lower risk of weight gain compared to other atypical antipsychotics. The case of an acute and excessive weight increase in a female first-episode schizophrenic patient who was treated with amisulpride monotherapy is reported. The improvement in psychopathology was remarkable. However, the patient gained 12.9 kg of body weight in the first 2 months of amisulpride administration and a total of 17.3 kg, 6 months after initiation of the treatment. Glucose and insulin levels, as well as a glucose tolerance test, remained normal throughout the observation period.     

Venlafaxine compared with fluoxetine in outpatients with depression and concomitant anxiety

The aim of this double-blind study was to compare the efficacy and safety of venlafaxine vs. fluoxetine in the treatment of patients with depression and anxiety. A total of 146 moderately depressed patients with associated anxiety were randomized to receive 75 mg/d venlafaxine or 20 mg/d fluoxetine for 12 wk. Dose increases were permitted after 2 wk of treatment, to 150 mg/d venlafaxine and 40 mg/d fluoxetine, to optimize response. At the final visit, a statistically significantly greater efficacy of venlafaxine over fluoxetine was observed on depressive symptoms and concomitant anxiety, and 75.0 and 50.7% of patients administered venlafaxine and fluoxetine, respectively, showed an overall response. A sustained response (for at least 2 wk), present at the end of the study was achieved in 57.8 and 43.3% of patients in the venlafaxine and fluoxetine groups, respectively, and at the final visit, 59.4 and 40.3% of patients, respectively, were in remission (virtually asymptomatic). Dose increases were required by a greater percentage of patients in the fluoxetine group (52.9%), than in the venlafaxine group (37.1%), and in those patients whose dose was increased, a higher efficacy was again observed with venlafaxine. Venlafaxine and fluoxetine were well tolerated, with the most frequently experienced adverse events being nausea and headache. Fewer patients in the venlafaxine group than in the fluoxetine group reported at least one adverse event (55.7 and 67.1% patients, respectively). Venlafaxine therefore proved to be significantly more effective than fluoxetine in improving depressive symptoms and concomitant anxiety.     

Association study of olanzapine-induced weight gain and therapeutic response with SERT gene polymorphisms in female schizophrenic patients

We investigated the relationships between L/S promoter (SERTPR) and l/s intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with olanzapine-induced weight gain and treatment response in 94 female schizophrenic patients treated with olanzapine for up to 3 months. Body mass index (BMI) was calculated for each patient prior to olanzapine administration and 3 months afterwards. To assess and evaluate improvement of clinical psychotic symptoms and therapeutic response to the antipsychotic, all patients were rated using the Positive and Negative Syndrome ScaLe (PANSS). Overall, the presence of S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain in subjects who were non-obese at the time of admission. The presence of L SERTPR variant was associated with significantly better treatment response measured with total PANSS and general PANSS subscale, while the presence of l SERTin2 variant determined better treatment response only in several items. No evidence of linkage disequilibrium between the two loci was found in the sample. These findings identify genetic factors associated with oLanzapine-induced weight gain and treatment response in femaLe schizophrenic patients.     

Anger attacks in depressed outpatients and their response to fluoxetine.

"Anger attacks" are spells of anger that are inappropriate to the situation and have physical features resembling panic attacks. The Anger Attacks Questionnaire, designed to assess these attacks, was administered to 79 consecutive patients (25 men and 54 women, mean age 38.8 +/- 10.3 years) diagnosed as having major depression with the Structured Clinical Interview for DSM-III-R. Of these 79 depressed patients, 34 (13 men and 21 women) reported having anger attacks according to our criteria. The prevalence of anger attacks in a group of 31 younger depressed patients (48%) was significantly higher (p = .048) than that of 29 normal controls (21%) of similar age. Of the 79 depressed patients, 19 (7 men, 12 women) were treated openly with fluoxetine at 20 mg/day for at least 8 weeks. At pretreatment, 9 patients (47%) had reported anger attacks, only 3 (16%) continued to report them after treatment, and the difference was statistically significant (p less than .05).     

Effect of nizatidine on olanzapine-associated weight gain in schizophrenic patients in Korea: a pilot study

A pilot study was conducted to evaluate the effect of nizatidine on olanzapine-associated weight gain (OAWG) in ten patients with schizophrenia and schizophreniform disorder in Korea. Psychometric ratings with positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) were measured at baseline, week 4 and week 8; as were weight and body mass index (BMI). A combination of nizatidine for 8 weeks resulted in significant reversal of weight gain without worsening the psychopathology (weight: 3.5% and BMI: 3.7%). In line with studies of Western populations, an add-on therapy of nizatidine could be an effective option for the control of weight gain in olanzapine-treated patients in Korea. Our findings call for further evaluation of the effect of this drug on OAWG, with randomized placebo-controlled studies, in Asian populations.     

Pharmacogenetics of antipsychotic-induced weight gain.

Weight gain appears to be a serious side effect encountered during treatment with many antipsychotic drugs. Although the propensities of inducing weight gain vary considerably between antipsychotics, weight gain is mostly observed in atypical antipsychotics, increasingly prescribed for a variety of psychiatric disorders. Beside the psychological consequences weight gain may influence patients' compliance and secondary medical comorbidities related to being overweight may arise, including diabetes, hypertonia, respiratory problems, and some types of cancer. Obesity research generally suggests that a complex system of neurotransmitters, neuropeptides, hormones and immune related factors interact in neural circuits involving at least the hypothalamus, the solitary tract and cortical structures to regulate energy homeostasis and body weight. Antipsychotics that have weight gain inducing properties may disrupt associated pathways at any of these levels, although it remains unclear what the mechanisms of action might be. Given the potential deleterious effects of weight gain, individual predictors of weight gain would be extremely helpful at the beginning of pharmacological treatment with atypical antipsychotics, allowing obesity to be avoided or for counteractive steps such as dietary restrictions to be taken in predisposed individuals. So far, only a few predictors to detect individuals at high risk have been reported and these have limited power. It is likely that genetic factors play a major role in determining individual response to antipsychotics as well as their side effect profile. In this article, we have reviewed literature related to antipsychotic-induced weight gain and have discussed the major issues, before updating the reader on current obesity research findings. Finally, we emphasize previous studies relating to the pharmacogenetics of antipsychotic-induced weight gain.     

Acquisition and retention of skills training methods in chronic schizophrenic outpatients.

Forty-one DSM-III-R schizophrenic subjects on constant, low-dose maintenance neuroleptic drug therapy (5-10 mg of fluphenazine decanoate intramuscularly every 2 weeks) were randomly assigned to structured and modularized skills training or to supportive group psychotherapy. The skills training was designed by using cognitive and behavioral methods to compensate for the learning disabilities that plague many schizophrenic patients. Skill acquisition was assessed by using quantified performance on standardized role-play tests. Subjects who received skills training made significant gains in each of the areas taught, whereas those who participated in the control psychotherapy group did not. The knowledge and skills learned during training were retained without significant erosion over a 1-year followup period. These results suggest that the use of structured principles of learning and cognitive therapy can effectively train schizophrenics in skill areas pertinent to the self-management of their illness.     

Amantadine for weight gain associated with olanzapine treatment.

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.     

A double-blind comparison of fluoxetine, imipramine and placebo in outpatients with major depression

Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 outpatients with DSM-III major depression, of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy. Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo. Both imipramine and fluoxetine were significantly superior to placebo on most measures. There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures. Fluoxetine was generally well tolerated. Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant. The results support previous studies which suggest fluoxetine's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs.     

抗精神病药物所致体重增加与多巴胺D2受体基因多态性和治疗效应的关联分析

目的　探讨抗精神病药物 (APS)所致体重增加与多巴胺D2 受体 (DRD2 )基因TaqIA多态性和治疗效应之间有无相关。方法　采用PCR RFLP方法分析 117例首发精神分裂症患者DRD2 基因TaqIA多态性 ,APS(氯丙嗪或利培酮 )单药治疗 10周 ,测定患者治疗前后体重和体重指数 (BMI) ,用阳性和阴性症状量表 (PANSS)评定患者治疗前后精神症状 ,并分析BMI变化值与基因型和PANSS减分率的相关性。结果　治疗后患者平均体重变化 (3 15± 3 47)kg或基础体重的(5 6 9± 6 15 ) % ,体重变化的范围为 - 7kg～ 12kg或 - 7 78%～ 32 43% ;患者年龄和基础BMI明显影响BMI变化值 ,差异有显著性 (P =0 0 3)和非常显著性 (P =0 0 0 0 1) ;A1等位基因和PANSS减分率对BMI变化值的影响差异均无显著性 (P >0 0 5 )。结论　DRD2 基因TaqIA多态性不可能是APS所致精神分裂症体重增加的主要遗传因素 ;体重增加不是APS临床治疗效果的指标。